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The southern terminus of the Piraeus–Platy railway is at the harbour of Piraeus, where connections with ferries to several Greek islands exist. From Piraeus the line run northeast towards the centre of Athens, where it crosses the main Athens Railway Station, the former Larissa station. Continuing through the northern suburbs of Athens, the line runs to Agioi Anargyroi, where the Peloponnese line used to branch off westwards. The narrow gauge track is still in place from this point on.

After a couple of kilometers the line passes Acharnes Railway Center (SKA), the junction connecting the main line with the Proastiakos line to Athens International Airport "El. Venizelos" and with the new standard gauge line towards Kiato in the Peloponnese. The main line continues northwards, climbs steadily towards Oinoi, through rural and wooded countryside, typical of northern Attica. There is a 22 kilometres (14 mi) branch line from Oinoi to Chalcis.

From Oinoi to Tithorea, the double-track rail line allows high speed transit of the flat Thiva plain; while from Tithorea, the line reverts to single-track as it climbs alongside Mount Parnassus from Amfikleia to Bralos and then descending to Leianokladi. There is a 23 km branch line from Leianokladi passing through Lamia to Stylida. The mountain scenery on this single track section of the line, which extends from Bralos to Domokos, is noted for being spectacular.

From Domokos to Thessaloniki, trains are able to run on high speed electrified double track line.[1] At Palaiofarsalos, an 80 km line to Karditsa, Trikala and Kalampaka branches off (former Thessaly Railways). There is also a metre gauge line to Velestino, which is not used anymore commercially. At the Thessalian capital Larissa there is a 61 km branch line to Volos. North of Larissa, the line passes through a tunnel at Tempe. The picturesque line adjacent to the coast near Platamon at the northern end of Tempe to Katerini is now abandoned, though still visible. This section of the line provides passengers with unique views towards mountains and sea as the train travels along the eastern slopes of Mount Olympus to Katerini.

Platy, 472 kilometres (293 mi) North of Athens and 48 km to the West of Thessaloniki, is the point where Athens and Thessaloniki were first linked by rail in 1916. Trains commenced operations between the two cities in 1918, the first through train service from Athens to Paris linking up with the Orient Express, which was inaugurated in 1920. The line joins with the line from Thessaloniki to Amyntaio, Kozani, and Florina.

Larissa and Thessaloniki have substantial marshalling yards for both goods and passenger trains. Journey time between Athens and Thessaloniki can vary depending on the type of train selected. The stopping service regular train service takes approximately 6 hours, while the Express takes 5 hours and 30 minutes. The InterCity (IC) rail service usually takes about 5 hours.
When updates on the whole of the railway corridor are finished (2016-2017), the whole trip will take about 3 hours.

Although a railway line from Athens to the north had been planned since 1883, the first section from Athens to Demerli (current Palaiofarsalos railway station) was not opened until 1908. The two branch lines from Schimatari to Chalcis and from Lamia to Stylida were also opened in 1908. Subsequently, the line was extended towards the former Greek-Turkish border at Papapouli, between Larissa and Katerini. Finally in May 1916, the remaining section from Papapouli to Platy on the line from Thessaloniki to Monastir (Bitola) was opened.[3]

Starting with the late 1980s, the line has been contiunously upgraded, to make sure it keeps up with the demands of the railway circulation. The first upgrade was west of Oinoi in the early 1990s. In 1996 the Orfana bypass was opened. In November 2003, the Tempi Valley line was abandoned in favour of a tunnel and in 2004 the Tempi-Platamon-Katerini-Platy section was drastically shortened, leading to the abandonment of a picturesque route next to the Aegean Sea at Platamon. Between 2005 and 2010 several sections have been upgraded in order to allow for higher speed, notably the sections Oinoi – Tithorea, Domokos – Larissa and Aiginio – Thessaloniki,[4] and the section Evangelismos - Leptokarya.[5] Currently, the Tithorea-Domokos part is being reconstructed (partly in different route, shortening it from 122 to 106 km) in order to sustain high-speed railway requirements. This part contains 2 tunnels (the 9 km Kallidromo tunnel -the longest in the Balkans- and the 6.5 km Othrys tunnel) and it will be ready in 2018.[6] Another upgrade is the reparation of the damaged electrification of the section Acharnes - Tithorea.[1]